Abstract
Immunotherapy targeting immune checkpoint molecules has provided remarkable clinical benefits in cancer patients but no clinically relevant biomarker for predicting treatment outcomes exists. Recently, we demonstrated that glycan structures of serum α1-acid glycoprotein (AGP) changed dramatically in cancer patients and that α1,3fucosylated AGP (fAGP) levels increased along with disease progression and decreased responding to chemotherapy treatments. Here, the fAGP was analyzed in sera prospectively obtained from 39 patients with advanced lung cancer who underwent immunotherapy with anti-PD-1 antibody, nivolumab. Twenty-three patients had significantly high fAGP levels above the cut-off value (H-fAGP) at one month after starting the treatment and 20 patients in this group, whose tumor sizes did not decrease, maintained high fAGP levels continuously and subsequently died. However, the other 16 patients, whose fAGP levels decreased or maintained below the cut-off value (L-fAGP), survived during a 2-year observation even though 5 patients in this group had no tumor shrinkage. Accordingly, the overall survival rate was found to significantly correlate with the fAGP level. Multivariate analyses revealed that the H-fAGP was an independent risk factor for cancer progression. Therefore, the fAGP level appeared to be a reliable biomarker for predicting clinical efficacy of immunotherapy with nivolumab.
Highlights
Inhibitory therapeutic strategies targeting immune checkpoints such as cytotoxic T lymphocyte antige-4 (CTLA4)[1], programmed cell death-1 (PD-1)[2] and its ligand (PD-L1)[3] have been proposed by their blockades with anti-CTLA-44, anti-progressive disease (PD)-1 and anti-PD-L1 antibodies[5,6], respectively
It was of particular interest that recurrence and/or metastasis occurred in patients who had been undergoing chemotherapies and/or radiation after operation was detected by elevated levels of fucosylated glycans in serum AGP (FUCAGP) in advance before their determinations with computerized tomography (CT) scans and diagnoses with conventional tumor markers
Changes in the fucosylated AGP in serum (fAGP) level determined at baseline and one month after starting nivolumab administration were compared in respective patients who are originally classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria[28]
Summary
Inhibitory therapeutic strategies targeting immune checkpoints such as cytotoxic T lymphocyte antige-4 (CTLA4)[1], programmed cell death-1 (PD-1)[2] and its ligand (PD-L1)[3] have been proposed by their blockades with anti-CTLA-44, anti-PD-1 and anti-PD-L1 antibodies[5,6], respectively. We developed a MALDI-TOF-MS system with a novel operation software (AGPAS) to analyze glycan structures of AGP comprehensively and determined a relative abundance of α1,3fucosylated glycans with tri- and tetraantennary glycan chains in AGP (FUCAGP)[25,26]. It was found, for the first time, that α1,3fucosylated AGP could be an appropriate marker of disease progression and prognosis in various cancer patients, and that abnormally high levels of FUCAGP were found in patients with esophagus, stomach, lung, breast, liver, pancreas, colon and rectum carcinomas who had a poor prognosis[25,26]. We measured fAGP in serum samples from patients with advanced lung cancer who received immunotherapy with anti-PD-1 antibody, nivolumab after repeated treatments with unsuccessful chemotherapies, and evaluated the fAGP as a potential biomarker for treatment responses and outcomes
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